Adrostano-pyridines and their preparation



United States Patent 'Oflice 3,409,609 Patented Nov. 5, 1968 3,409,609 ADROSTANO-PYRIDINES AND THEIR PREPARATION Theodore C. Miller, East Greenbush, N.Y., assignor to Sterling Drug Inc., New York, N.Y., a corporation of Delaware N Drawing. Filed Dec. 24, 1964, Ser. No. 421,090 24 Claims. (Cl. 260-239.5)

ABSTRACT OF THE DISCLOSURE Androstano[3,2-b]-6'-R-pyridines and androstanofi 7, l 6- b]-6-R-pyridines are prepared by pyrolysis of 2-(3-R-allylidene)-3-oximinoandrostanes and l6-(3-R-allylidene)- 17-oximinoandrostanes, respectively, where R is loweralkyl, phenyl, furyl or thienyl. The final products where p R is furyl can be ozonized to give compounds where R is carboxy, and the latter decarboxylated to afford compounds where R is hydrogen. Also disclosed is the preparation of bis(17B-oxyandrostano[3,2-b:2',3'-e] )pyridines.

wherein R is hydrogen, carboxy, lower-alkyl, phenyl, furyl or thienyl; R is hydrogen or methyl; and Z is C=O, CH(OH-;3), C(lower-alkyl)(OH-B), CH(OAcyl-;3), or C(lower-alkyl)(OAcyl-fi)," Acyl being carboxylic acyl having from 1 to 10 carbon atoms; including compounds of the above formula having one double bond in the 4,5- position, or two double bonds, one in the 4,5-p0sition and the other in the 6,7-position.

The term lower-alkyl as used hereinrefers to alkyl groups having from one to six carbon atoms, including such radicals as methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl.

The term Acyl as used herein refers to acyl radicals derived from carboxylic acids having from one to ten carbon atoms and a molecular weight less than 200. Representative of the acyl radicals which can be present are lower-alkanoyl, e.g., formyl, isobutyryl, caproyl, heptanoyl, octanoyl, trimethylacetyl, and the like; carboxylower-alkanoyl, e.g., succinyl 3-carboxypropionyl); cycloalkyl-loWer-alkanoyl wherein cycloalkyl has 5-6 ring members, e.g., B-cyclopentylpropionyl, S-cyclohexylpropionyl, and the like; benzoyl; phenyl-lower-alkanoyl or -alkenoyl, e.g., phenylacetyl, B-phenylpropionyl, cinnamoyl, and the like; phenoxy-lower-alkanoyl, e.g., pchlorophenoxyacetyl; and pyridylcarbonyl, e.g., nicotinoyl and isonicotinoyl. In acyl radicals containing a phenyl group, the latter can be unsubstituted or substituted by from one to three substituents inert under the reaction conditions used, including lower-alkyl, lower-alkoxy, halogen (including fluorine, chlorine, bromine and iodine) and nitro.

In compounds of Formula I wherein R is phenyl, furyl or thienyl, these groups can be either unsubstituted or substituted by from one to three substituents inert under the reaction conditions used, including lower-alkyl, loweralkoxy, halogen and nitro. When R is furyl (or thienyl) it can be either 2-furyl (2-thieny1) or 3-furyl (3-thienyl).

The compounds of Formula I wherein R is loweralkyl, phenyl, furyl or thienyl, R' is hydrogen or methyl, and Z is CH(OH- 8), C(lower-alkyl) (OH-p), CH (OAcylp), or C(lower-alkyl) (OAcyl-p), including 4-unsaturated and 4,6-di-unsaturated compounds, are prepared according to the following series of reactions:

BIO-N ,A 3-oxo steroid of Formula II is condensed with 3-R- acrolein in the presence of a strong base, for example, an alkali metal hydroxide, alkoxide or amide to give a 2-(3- R-allylidene)-3-oxo steroid of Formula III. The latter is converted to its oxime (IV) which upon heating is cyclized to a compound of Formula I. The cyclization takes place at a temperature above the melting point of preferably between about 200 and 250 C.:

The intermediates of Formulas III and IV, including compounds wherein the oximino group is acylated, are novel classes of compounds and are within the purview of the invention.

The compounds of Formula I wherein R is hydrogen are prepared by subjecting a compound of Formula I wherein R is 2-furyl to ozonolysis to give the corresponding compound wherein R is carboxy, followed by decarboxylating the latter by heating it above its melting point, preferably between about 200 and 250 C.:

HOOC

Zais CH(OH-p) byconventional oxidationtreactions, as l or thienyl; R is hydrogen or methyl; and Z is C=O, CH(OH), or CH(OAcyl), Acyl being carboxylic acyl having from 1 to 10 carbon atoms; includingcompounds of the above Formula V wherein Z is C=O and having a double bond in the 4,5-position, and compounds wherein Z is CH(OH) or CH(OAcyl) and having a double bond in the 5,6-position. The saturated compounds of Formula V can belong to either the 5aor Sfl-series; and in compounds wherein Z is CH(OH) or CH(OAeyl) the oxy group can have either the aor fi-configuration.

The terms "lower-alkyl and Acyl and the groups represented by R have the same definition and scope as given above in connection with the compounds of Formula I.

The compounds of Formula V wherein R is loweralkyl, phenyl, furyl or thienyl, R is hydrogen or methyl, and Z is CH(OH) or CH(OAcyl), including 5,6-unsaturated compounds, are prepared by a series of reactions analogous to that used in preparing the compounds of Formula I, as follows:

HONH:

VIII

where R is hydrogen, carboxy, lower-alkyhphenyl, furyl 16-r(3-R-allylidene):lLoxo .steroid of FormulaNII. The latter is converted to its oxime (VIII) which upon heating is cyclized to a compound of Formula V. The cyclization takes place at a temperature above the melting point of the oxime, preferablybetween about 200 and 250 C. a .-'-1 J g The intermediates "of Formula VIII, including compoundswherein the oximin'o group is acylat ed, are novel classes of compounds andare'within the purview of 'the invention. The compounds of Formula V wherein R is hydrogen are prepared by subjecting a compound of Formula V wherein R is 2-furyl to ozonolysis to give the corresponding compouud wherein R ,is carboxy, {followed by decarboxylating the latter by heating it above its melting point, preferably between about 200" and 250 C.:

' COOH H1" The compounds of Formula V wherein Z is C=O are prepared from the corresponding compounds wherein Z is CH(OH) by conventional oxidation reactions, as by use of chromic oxide or by the Oppenauer method.

I Still another aspect of the invention resides in cornpounds of the formula wherein R" is hydrogen or lower-alkyl, and Y is hydrogen or Acyl. The terms lower-alkyl and Acyl have the same definition and scope as given above in connection with the compounds of Formula I.

The compounds of Formula IX are prepared by reacting with hydroxylamine a compound of the formula The compounds of Formula X are in turn prepared by reacting with formaldehyde a 2-hydroxymethylene-3-oxo steroid of the formula joy The compounds of the invention are basic in nature and thus form acid-addition salts when treated with a moderate to strong inorganic or organic acid. These salts are the full equivalent of the corresponding free bases insofar as the physiological properties inherent in the cation are concerned. Both the free base and salt forms are considered to be one and the same invention.

The structures of the compounds of the invention were established by the modes of synthesis, by elementary analysis and by ultraviolet and infrared spectral data.

Biological evaluation of the compounds of Formulas I, III, IV (including esters thereof), V, VII, VIII (including esters thereof) and IX, has shown that they possess endocrinological properties, for example, anti-estrogenic, anabolic, androgenic, minerocorticoid modifying and desoxycorticosterone acetate potentiating activities; and pharmacological properties, for example, cardiovascular activity.

The following examples will further illustrate the invention without the latter being limited thereby.

EXAMPLE 1 2-cinnamylidene-5a-androstan-17,B-ol-3-one [III; R is C6H5, R IS CH3, Z IS A mixture of 14.52 g. (0.0500 mole) of Set-androstan- 17fi-ol-3-one and 3.30 g. (0.0500 mole) of 85% potassium hydroxide was dissolved by heating in 250 ml. of methanol. The solution was cooled to room temperature and 13.20 g. (0.100 mole) of cinnarnaldehyde was :added. The reaction mixture was stirred for seventy minutes at room temperature and for sixty minutes at ice-bath tem perature. The solid product was collected by filtration. washed with cold methanol and dried in vacuo at 60 C. to give 16.41 g. of 2-cinnamylidene-Sat-androstan-17 3-01 3-one, yellow needles, M.P. 180.0181.0 C. (corr.) when recrystallized from ethyl acetate; [a] =+60.0 (1% in chloroform); ultraviolet maxima at 233 and 337 mp. (E=9,000 and 35,500).

By replacing the cinnamaldehyde in the foregoing preparation by a molar equivalent amount of crotonaldehyde, fi-(3-furyl)acrolein, ,B-(Z-thienyDacrolein, fi-(3-thieny1) acrolein, 4-rnethylcinnamaldehyde or 4-fluorocinnamaldehyde, there can be obtained, respectively,

2- Z-butenylidene) -5a-androstan- 1 75-01-3 -one,

2- [3 3 -furyl) allylidene]-5oc-andr0stan-17/3-0l-3-0ne,

2- 3- 3 -thienyl allylidene]-5ot-androstan-17B-o1-3 -one, 2-(4-methylcinnamylidene) -5a-androstan-17/8-ol-3-one or 2-(4-fluorocinnamylidene) -5u-androstan-1 7,8-01-3 -one.

By replacing the 5a-androstan-l7,8-01-3-one in the foregoing preparation by a molar equivalent amount of 19- nor-5a-androstan-17B-ol-3-one, 4-androsten-17fl-ol-3-one, or 4,6-andrstadien-17,8-01-3one, there can be obtained, respectively, Z-cinnamylidene 19 nor-a-androstan-l7fiol-3-one, 2-cinnamylidene-4-androsten17fl-ol-3-one, or 2 cinnamylidene-4,6-androstadien-17fl-ol-3-one.

2-cinnamyIidene-Sa-androstan-17,8-ol-3-one (4.05 g.), 0.19 g. of p-toluenesulfonic acid and 11 ml. of ethylene glycol in 150 ml. of benzene was heated at reflux for six hours under a water separator. The reaction mixture was washed with saturated sodium bicarbonate solution and the organic layer separated and washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from ether and from ethyl acetate to give the ethylene glycol ketal of Z-cinnamylidene-Sa-andrOstan-I7,6-ol-3-one, colorless needles, M.P. 203.8205.0 C. (corr.); [a] =+47.5 (1% in chloroform).

EXAMPLE 2 17B-acetoxy-2-cinnamylidene-5a-androstan-3-one [III; R is C H R is CH Z is CH(OCOCH -/3)] A mixture of 1.01 g. (0.0025 mole) of Z-cinnamylidene-Sa-androstan-17 8-ol-3-0ne, 5 ml. of acetic anhydride and 10 ml. of pyridine was heated on a steam bath for thirty minutes. The reaction mixture was poured into ml. of ice-water, and the solid product was collected, dried, and recrystallized first from an ethyl acetate-hexane mixture and then from an ethyl acetate-ethanol miX- ture to give l7/3-acetoxy-Z-cinnamylidene-5a-androstan-3- one, yellow needles, M.P. 227.0-2280 C. (corr.), [a] =+0.3 (1% in chloroform); ultraviolet maxima at 233 and 388 m (e=6,800 and 34,900).

By replacing the acetic anhydride in the foregoing preparation by a molar equivalent amount of caproyl chloride, succinic anhydride, fi-cyclohexylpropionyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, phenylacetyl chloride, p-chlorophenoxyacetyl chloride, cinnamoyl chloride or nicotinoyl chloride, there can be obtained, respectively,

17,6-caproyloxy-2-cinnamylidene-5u-androstan-3 -one, 17;?- (fi-carboxypropionoxy) -2-cinnamylidene-5aandrostan-3 -one, 17,8- ,B-cyclohexyl pro pionoxy) -2-cinnamylidene-5 aandrostan-3-one, 17 3-benzoyloxy-2-cinnamylidene-5a-androstan-3-one, 17,8- (p-nitrobenzoyloxy -2-cinnamylidene-5a-androstan- 3 -one, 17/3-phenylacetoxy-2-cinnamylidene-5a-androstan-3 -one, 17,8- (p-chlorophenoxyacetoxy) -2-cinnamylidene-5aandrostan-B-one or 17,6-cinnamoyloxy-2-cinnamylidene-5x-androstan-3-one or 17,8-nicotinoyloxy-Z-cinnamylidene-Sa-androstan-3-one.

EXAMPLE 3 2-[3-(2-furyl)allylidene]-5u-androstan-17,8-ol 3 one [III; R is 2-furyl, R is CH Z is CH(OH- 8)] was prepared from 2.90 g. of Soc-EIIIGIOSifiII-17,3-01-3-0116 and 1.34 g. of fl-(2-furyl)acrolein according to the procedure described above in Example 1. The product was recrystallized from a mixture of methylene dichloride and methanol to give 2-[3-(2-furyl)'allylidene]-5ot-androstan-17,8- ol-3one, M.P. 192194 C. (uncorn).

EXAMPLE 4 Z-cinnamylidene-l7a-methyl-5a-androstan 17 3 o1 3- one [111; R is C H R is CH Z is C(CH (OH-,8)] was prepared from 18.27 g. of 17amethyl-5u-androst-an-17;?- ol-3-one and 8.7 g. of cinnamaldehyde according to the procedure described above in Example 1. An amorphous product was obtained which was converted directly to the oxime in Example 8 below.

EXAMPLE 5 2- 3 -(2-furyl) allylidene]-17a-methyl-5ot-androstan-17,8- ol-3-one [III; R is 2-furyl, R is CH Z is was prepared from 24.36 g. of 17a-methyl5a-androstan 17 3-ol-3-one and 10.27 g. of fi-(2-furyl)acrolein according to the procedure described above in Example 1. The product was recrystallized from a mixture of chloroform :and ethanol to give 2-[3-(2-furyl)allylidene]-l7tx-methyl- Sea-androStan-l7fi-ol-3-one in the form of a hemi-ethanolate, yellow needles, MJP. 250.8253.7 C. (dec.) (corr.); [a] =+23.6 (1% in chloroform); ultraviolet maximum at 360 mu (e=35,800).

2- [3-(2-furyl) allylidene] -17a-methyl-5a-androstan-17B- ol-3-one can be caused to react with acetic anhydridepyridine, by heating at 100 C., to give 17fl-acetoxy-2-[3- (Z-furyl) allylidene] -17a-methyl-5a-androstan-3-one.

EXAMPLE 6 2-cinnamylidene-5a-androstan-17,8-ol-3-one oxime [IV; R is C H R is CH Z is CH(OH-fi)] A mixture of 8.09 g. (0.20 mole) of Z-cinnamylidene- Sa-androstan-l7 8-ol-3-one, 2.78 g. (0.040 mole) of hydroxylamine hydrochloride, 100 ml. of ethanol and 25 ml. of pyridine was heated at reflux for four hours. The

2- (Z-butenylidene) u-androstan- 17 B-o1-3-one,

2- 3- (3-furyl) allylidene] -5 a-androstan- 17 fl-ol-3-one,

2- [3- (Z-thienyl allylidene] -5 a-androstan- 17 fl-ol-3-one, 2- 3- 3 -thienyl) allylidene] -5ot-androstan- 17 fi-ol-3-one, 2- (4-methylcinnamylidene -5 u-androstan- 17 5-ol-3-one, 2- (4-fluorocinnamylidene -5 u-androstan- 17 B-ol-3 -one, Z-cinnamylidene-19-nor-5x-androstan-17B-ol-3-one, 2-cinnamylidene-4-androstan-17 B-ol-3-one, or 2-cinnamylidene-4,6-androstadien- 17 5-ol-3-one,

there can be obtained, respectively,

2- (Z-butenylidene -5 a-androstan- 17 B-ol-3-one oxime, 2- [3- 3-furyl) allylidene] -5 a-androstan- 17,8-01-3-one oxime, 2-[3-(2-thienyl) allylidene]-5a-androstan-175-ol-3-one oxime,

2- [3- (3-thienyl) allylidene] -5 a-androstan- 1713-01-3 -one oxime,

2- (4-methylcinnamylidene -5 a-androstan- 17 ,B-ol-3-one oxime,

2- (4-fiuorocinnarnylidene) -5 u-andro stan-17p-ol-3-one oxime,

2-cinnamylidene-19-nor-5 a-androstan-17 B-ol-3-one oxime,

2-cinnamylidene-4-androstan-17 [3-01-3 -one oxime, or

2-cinnarnylidene-4,6 androstadien-17 [3-ol-3-one oxime.

A mixture of 1.00 g. of 2-cinnamylidene-5u-androstan- 17p-o1-3-one oxime, 5 ml. of acetic anhydride and m1. of pyridine was heated on a steam bath for two and onehalf hours. The reaction mixture was poured into 200 ml. of ice-water with stirring, and the product was collected by filtration, washed with water and dried. After recrystallization from methanol there was obtained 2- cinnarnylidene-5ot-androstan-17B-ol-3-one oxime diacetate in the form of yellow prisms, M.P. 188.4196.0 C. (corr.); [a] =42.9 (1% in chloroform); ultra- 231 and 325 mu (-e=11,500 and 34,- 200); infared absorption at 3.47, 5.69, 5.80, 6.17, 6.28, 6.40, 6.72, 6.82 and 692a.

EXAMPLE 7 2 [3 (2-furyl) allylidene]-5u-androstan-17i3-ol-3-one oxime [IV; R is 2-furyl, R is CH Z is CH(OH-B)] was prepared from 1.29 g. of 2-[3-(2-furyl) allylidene]-5aandrostan-17B-ol-3-one and 0.45 g. of hydroxylamine hydrochloride according to the procedure described above in Example 6. The product was recrystallized from a mixture of methylene dichloride and methanol to give 2-[3- (Z-furyl)allylidene]-5a-androstan-l7fi-ol-3-one oxime in the form of yellow needles, M.P. about 145 C. (uncorr.).

2 [3 (2-furyl)allylidene]-5x-androstan-17f3-ol-3'one oxime was heated with acetic anhydride and pyridine to give its diacetate, peach-colored prisms, M.P. 206.2- 208.0 C. (dec.) (corn) when recrystallized from a mixture of methylene dichloride and ethyl acetate; ]D =-46.0 (1% in chloroform).

EXAMPLE 8 2 cinnamylidene 17u-methyl-5a-androstan-175-ol-3- one oxime [IV; R is C H R is CH Z is C(CHg) (OH-[3)] was prepared from 2.00 g. of 2-cinnamy1idene- 17a-methyl-5a-androstan-17fi-ol-3-one and 0.63 g. of

hydroxylamine hydrochloride according described above in Example 6.

EXAMPLE 9 2 [3 (Z-furyl)allylidene]-17ot-methyl-5a-androstanl7 8-ol-3-one oxime [IV; R is 2-furyl, R is CH Z is C(CH (OH-M] was prepared from 26.68 g. of 2-[3-(2- furyl)al1ylidene] 17ot-methyl-5a-androstan-17fl-ol-3-one and 8.61 g. of hydroxylamine hydrochloride according to the procedure described above in Example 6. The product was recrystallized from a mixture of methylene dichloride and methanol to give 2-[3-(2-furyl)allylidene]- l7u-methyl-5a-androstan-17fl-ol-3-one oxime, M.P. about C. (uncorr.).

2 [3 (2-furyl)allylidene]-17a-methyl-5a-androstanl7/3-ol-3-one oxime can be converted to its diacetate by heating with an excess of acetic anhydride in pyridine.

EXAMPLE 10 17l3-hydroxy-5a-androstano[3,2-b]-6-phenylpyridine [1; R is C H R is CH Z is CH(OH-;3)]

Z-cinnamylidene-Sa-androstan--ol-3-one oxime was heated in a Woods metal bath at 20-245 C. for ninety minutes under water-aspirator vacuum. The product was cooled and recrystallized first from a mixture of chloroform and ethyl acetate and then from a mixture of methylene dichloride and ethyl acetate to give 1713- hydroxy-5 a-androstano [3 ,2-b] -6-phenylpyridine, yellow plates, M.P. 239.2242.0 C. (corr.); [oc] =+63.6 (1% in chloroform); ultraviolet maxima at 248 and 287 m (e==14,100 and 13,300); infrared absorption at 3.03, 3.47, 5.75, 6.31, 6.40 and 6.80

By replacing the 2-cinnamylidene-5a-androstan-17,6-01- 3-one oxime in the foregoing preparation by a molar equivalent amount of to the procedure 2- (Z-butenylidene -5 u-andr0stan-17 fl-ol-3-one oxime, 2- [3- 3-furyl) allylidene] -5 ot-androstan-17 fl-ol-3-one oxime,

2- 3- Z-thienyl) allylidene] -5a-androstan- 17 8-01-3 -one oxime,

2- [3-( 3-thienyl) allylidene] -5 a-andr0stan-17fl-ol-3-one oxime,

2-(4-methylcinnamylidene) -5 a-androstan-17 (3-ol-3 -one oxime,

2- (4-fiuorocinnamylidene) -5a-androstan-17flol-3 -one oxime,

Z-cinnamylidene- 19-nor-5 u-androstan-17 8-01-3 -one oxime,

2-cinnamylidene-4-androsten- 17 fl-ol-3-one oxime, or

Z-cinnarnylidene-4,6-androstadien- 17 fi-ol-3-one oxime,

there can be obtained, respectively,

17 B-hydroxy-S oz-androstano [3 ,2-b] -6'-methylpyridine,

17 B-hydroxy-S a-androstano 3 ,2-b] -6'- 3-furyl) pyridine,

17 B-hydroxy-S ot-androstano [3 ,2-b] -6'- (2-thienyl) pyridine,

17 a-hydroXy-S a-androstano [3 ,2-b] -6'-( 3-thienyl) pyridine,

17 fl-hydroxy-S a-androstano [3 ,2-b] -6-(p-tolyl) pyridine,

17 B-hydroxy-S a-androstano [3 ,2-b -6'- (4-fluorophenyl) pyridine,

17 B-hydroxy-19-nor-5 ot-androstano [3 ,2-b] -6- phenylpyridine,

17 fl-hydroxy-4-androsteno 3 ,2-b] 6'-phenylpyridine, or

17 fi-hydroxy-4,6-androstadieno[3 ,Z-b] -6-phenylpyridine.

EXAMPLE 11 17-oxo-5u-androstano[3,2-b]-6-phenylpyridine [I; R is C H R is CH-,-, Z is CO] EXAMPLE 12 2-[3-(2-furyl)allylidene]androstan-17 3-o1-3-0ne oxime (Example 7) was heated at 220 230 C. (0.1 mm.), the product collected by sublimation, and recrystallized from a methylene dichloride-methanol mixture to give 17,6- hydroxy-a-androstano [3,2-b] -6'-(2-furyl) pyridine, pale yellow crystals, M.P. 212.4-2144, C. (corr.),

ultraviolet maxima at .266 and 309 m (e=l5,800 and 18,600); infrared absorption at 2.95, 3.45-3.50, 5.77, 6.25, 6.31, 6.43, 6.68 and 6.87,u.-

EXAMPLE 13 17fl-acetoxy-5a-androstano[3,2-b] 6' (2-furyl)pyridine [I, R is 2-furyl, R is CH Z is CH(OCOCH -;3)] was prepared by treating 2.41 g. of 17B-hydroxy-5uandrostano[3,2-b] 6' (2-furyl) pyridine with ml. of acetic anhydride and 20 ml. of pyridine for twenty-four hours at room temperature. The product was collected and recrystallized from a mixture of methylene dichloride and acetonitrile'to give 17B-acetoxy-5a-androstano [3,2-b] 6 (2 furyl) pyridine, colorless prisms, M.P. 244.4-245.8 C. (corr.), [a] =+54.0; ultraviolet maxima at 266, 274 and 309 m (e=15,200, 13,600 and 18,000). I

By replacing the acetic anhydride in the foregoing preparation by a molar equivalent amount of caproyl chloride, succinic anhydride, fl-cyclohexylpropionyl chloride, benzoyl chloride, p-nitrobenzoyl chloride, phenylacetyl chloride, p-chlo rophenoxyacetyl chloride, cinnamoyl chloride or nicotinoyl chloride there can be ob tained, respectively,

1 7,3-caproyloxy-5a-androstan'o [3 ,2-'b] -6'- (2-furyl) pyridine,

17p- (fi-carboxypropionoxy) -5a-androstano 3,2-b] -6- (2-furyl pyridine,

17,8- (fl-cyclohexylpropionoxy) -5a-androstano[ 3,2-b]

6'- (2-furyl pyridine,

17 3-benzoyloxy-5a-androstano[3,2-b] -6'- (2afuryl) pyridine,

1713- (p-nitrobenzoyloxy) -5a-androstano [3,2-b] -6'- (2- furyl) pyridine, 3

17/3-phenylacetoxy-5u-androstano 3,2-b] -6'- (2-furyl) pyridine,

17 6- (p-chlorophenoxyacetoxy) -5a-androstano 3,2-b]

6'-( 2-furyl pyridine,

17fl-cinnamoyloxy-5a-androstano 3,2-b] -6- 2-furyl) pyridine or 17fl-nicotinoyloxy-5a-androstano 3,2-b] -6 (2-furyl) pyrdine.

EXAMPLE 14 17 ,B-hydroxy-17a-methyl-5a-androstano[3,2-b] -6'-phenylpyridine [I; R is C H R is CH Z is C(CH (OH- 3)] Z-cinnamylidene-l7a-methyl-5a-androstan 17,8 01-3- one oxime (Example 8) (12.08 g.) was heated at 210- 220 C. for one and one-half hours under, water aspirator vacuum and then for three hours under high vacuum (0.05 mm.). The product was sublimed and recrystallized from a mixture of methylene dichloride and ethyl acetate to give 176 hydroxy-17a-methyl-5a-androstano [3,2 b] 6' phenylpyridine, tan needles, M.P. 209.6- 211.8 C. (corr.), [a] =+42.9 (1% in chloroform); ultraviolet maxima at 248 and 287 m (e=14,400 and 13,500);

17 3-hydroxy-17a-methyl 5a phenylpyridine can be caused to react with an excess of acetic anhydride in pyridine by heating at C. to give 17 8-acetoxy 17a methyl-5ot-androstano[3,2-b]-6'- phenylpyridine.

androstano[3,2 b]-6'- EXAMPLE 15 17/3-hydr0xy-17u-methyl 5a androstano[3,2-b]-6'-(2- furyl) pyridine [1; R is 2-furyl, R is CH Z is C(CH -1 2-[3-(2-furyl)allylidene]-17a-methyl 50c androstan 17,8-ol-3-one oxime (Example 9) (8.00 g.) was heated at 210220 C. under nitrogen until the solid melted, then for two hours under water aspirator vacuum and finally for two hours at 210220 C. under high vacuum (0.03 mm.). The product was sublimed and recrystallized, repeatedly from a mixture of methylene dichloride and ethyl acetate to give 17 3-hydroxy-17u-methy1- 5a androstano[3,2 b] 6' (2 furyl) pyridine, brown prisms, M.P. 222.2-223.8 C. (corr.), [oz] =+49.0 (1% in chloroform); ultraviolet maxima at 266 and 309 m (e=l5,000 and 17,600); infrared absorption at 2.88, 3.20, 3.45, 5.80, 6.25, 6.32, 6.44, 6.69 and 6.86

EXAMPLE 16 '17fl-acetoxy-5a-androstano[3,2-b]pyridine [I; R is H, R is CH Z is CH(OCOCH 6)] A stream of ozone was passed through a stirred solution of 3.94 g. of 17fi-acetoxy-5a-androstano[3,2-b]-6'- (2-furyl) pyridine (Example 13) in 60 ml. of acetic acid and 30 ml. of ethyl acetate for sixty-four minutes (corresponding to 36.4 millimoles of ozone) at 5 to 0 C. There was then added 20 ml. of water dropwise followed by 2 ml. of 30% hydrogen peroxide, and the mixture was stirred for seventeen hours and poured with stirring into 2 liters of deionized water. The resulting 17p-acetoxy-5aandrostano[3,2-b]-6-carboxypyridine was collected by filtration, washed, dried, heated at 200-210 C. (0.5-0.1 mm.) for four and one-half hours and sublimed to give 17 3-acet0xy-5a-androstano[3,2-b]-pyridine, M.P. 137.2- 142.2 C. (corr.), [a] =+44.2 (1% in chloroform); ultraviolet maxima at 269 and 277 m,u (e=5,660 and 4,550).

Hydrogen chloride gas was pased through a solution of 17,8 acetoxy-5a-androstano[3,2 b]pyridine in ethyl acetate. The prepared product was separated and recrystallized from a mixture of methylene dichloride and ethyl acetate to give 17B-acetoxy-5u-androstano[3,2-b] pyridine in the form of its hydrochloride salt, M.P. 274.0-276.0 C. (dec.) (corr.), [a] =+36.2 (1% in chloroform).

EXAMPLE 17 17/3 hydroxy 17oz methyl 5a androstano[3,2- b]pyridine [I; R is H, R is CH Z is C(CH (OH 9)] was prepared by ozonolysis and decarboxylation of 6.77 g. of 17 3 hydroxy 17cc methyl 5a androstano[3,2- b] 6 (2 furyl)pyridine (Example 15) by the procedure described above in Example 16. The product was sublimed and chromatographed on a column of g. of silica gel. The column was eluted with ether-pentane 1:1 and ether-pentane 3:1 and the resulting product was recrystallized from a mixture of methylene dichloride and methanol to give 17,6 hydroxy 17a methyl 50c androstano[3,2 b]pyridine, beige rods, M.P. 194.8196.4 C. (corr.), [a] =+41.7 (1% in chloroform); ultraviolet maxima at 269 and 277 m (e=5,410 and 4,260).

EXAMPLE 18 16 cinnamylidene 5 androsten 313 ol 17 one stan 3a ol 17 -tively, 16 cinnamylidene 19 nor 5 androsten 319- 11 [VII; R is C l-I R is CH Z is CH(OH B), A 5] was prepared from 28.85 g. of 5 androsten 3B o1 17 one and 11.84 g. of cinnamaldehyde according to the procedure described above in Example 1. There was thus obtained 40 g. of 16 cinnamylidene 5 androsten 3B- ol-l7-one, M.P. 210.5-213.0 C. (uncorr.).

By replacing the cinnamaldehyde in the foregoing preparation by a molar equivalent amount of crotonaldehyde, B (3 furyl)acrolein, B (2 thienyl)acrolein, fl (3- thienyl) acrolein, 4 methylcinnamaldehyde or 4 fluorocinnamaldehyde there can be obtained, respectively,

16- (Z-butenylidene) -5-androsten-3 B-ol- 17-one,

l6- 3- (3-furyl) allylidene]-5-androsten-3fl-ol-17-one,

16- [3-(2-thienyl) allylidene] -5-androsten-3fl-ol-17-one, 16- [3- 3-thienyl) allylidene]-5-androsten-3B-ol-17-one, 16- (4-methylcinn amylidene -5 andro sten-3 B-ol- 17 -one, or 16- (4-fluorocinnamylidene -5 -andr sten-3 B-ol-17-one.

By replacing the androsten 3 8 ol 17 one in the foregoing preparation by a molar equivalent amount of 19 nor 5 androsten 35 ol 17 one or 5/3 androone there can be obtained, respecol 17 one or 16 cinnamylidene 5B androstan 3aol-17-one.

16 cinnamylidene 5 androsten 3,3 ol 17 one can be caused to react in pyridine solution with acetic anhydride, caproyl chloride, succinic anhydride, 5 cyclohexylpropionyl chloride, benzoyl chloride, p nitrobenzoyl chloride, phenylacetyl chloride, p chlorophenoxyacetyl chloride, cinnamoyl chloride or nicotinoyl chloride to give, respectively,

3fi-acetoxy-16-cinnamylidene-5-androsten-17-one,

3 B-caproyloxyl6-cinnamylidene-S-androsten- 17 -one,

3 [3- B-carboxypropionoxy) 16-cinnamylidene-5- androsten-17-one,

318- B-cyclohexylpropionoxy) -1 6-cinnamylidene-5- androsten-17-one,

3 fl-benzoyloxy-16-cinnarnylidene-S-androsten-17-one,

3 ,3- (p-nitrobenzoyloxy) -16-cinnamylidene-S-androsten- 17-one,

3 fl-phenylacetoxy-l6-cinnamylidene-S-androsten-17-one,

3 B- (p-chlorophenoxy acetoxy) -16-cinnamylidene-5- andro sten- 17 -one,

3 [i-cinnamoyloxy- 1 6-cinn amylidene-S -androsteu- 17-one or 3 [ft-nicotinoyloxy-16-cinnamylidene-5-androsten-17-one.

EXAMPLE 19 16 [3 (2 furyl)allylidene] 5 androsten 35 ol- 17 one [VII; R is 2 furyl, R is CH Z is CH(OH- 5), A 5] was prepared from 43.26 g. of 5 androsten- 3B o1 17 one and 18.32 g. of {3 (2 furyl)acrolein according to the procedure described above in Example 1. The product was recrystallized from amixture of methylene dichloride and ethyl acetate to give 16 [3 (2- furyl) allylidene] 5 androsten 3,8 ol 17 one, yellow prisms, M.P. 204.8-206.0 C. (corr.), [a] =232.5 (1% in chloroform); ultraviolet maxima at 238 and 359 mp. (6:3,250 and 38,200).

EXAMPLE 20 16 [3 (2 furyl)allylidene] 5a androsten 3B- ol 17 one [VII; R is 2 furyl, R is CH Z is CH(OH- [3)] was prepared from 116.2 g. of 5a androstan 01 17 one and 48.9 g. of 2 '7 furylacrolein according to the procedure described above in Example 1. The product was recrystallized from a mixture of methylene dichloride and ethyl acetate to give 16 [3 (2 furyl] allylidene] androstan 3B ol 17 one, yellow prisms, M.P.- 22S.0226.8 C. (corr.), [a] =-177.8 (1% in chloroform).

EXAMPLE 21 16 cinnamylidene 5 oxime [VIII; R is C H A 5] was prepared from 36.22 g. of 16 cinnamylidene- 5 androsten 3B ol l7 one (Example 18) and 12.48 g. of hydroxylamine hydrochloride according to the procedure described above in Example 6. The product was recrystallized from a mixture of methylene dichloride and methanol to give 16 cinnamylidene 5 androsten: 3B o1 17 one oxime, colorless needles, M.P. 262.8- 265.0" C., [a] =173 (1% in chloroform); ultraviolet maxima at 233 and 329 mp. (e=8,070 and 40,800).

By replacing the 16 cinnamylidene 5 androsten- 33 ol 17 one in the foregoing preparation by a molar equivalent amount of 16- (2-butenylidene) -5-androsten-3B-ol-17-one, 16- 3- 3-furyl) allylidene] -5-androsten-3fl-ol-17-one,

16-[3-(2-thienyl) allylidene]-5-androsten-3B-ol-17-one,

l6-[3-(3-thienyl)allylidene1-5-androsten-3/3-ol-17-onc, 1 6- (4-methylcinnamylidene) -5-androsten-3fl-ol-17-one,

' 16-(4-fluorocinnamylidene)-5-androsten-35-ol-17-one,

16-cinnamylidene-19-nor-5-androsten-35-ol-17-one, 16-cinnamylidene-5B-androsten-3or-ol-17-one, 35-acetoxy-16-cinnamylidene-S-androsten-17-one, 3fl-caproyloxy-l6-cinnamylidene-S-androsten-17-one, 3 p3- fl-carboxypropionoxy) -16-cinnamylidene-5- androsten-l7-one, 3 ;8-( fl-cyclohexylpropionoxy)-16-cinnamylidene-5- androsten-l7-one, 3;8-benzoyloxy-16-cinnamylidene-5-androsten-17-one, 3 [i- (p-nitrobenzoyloxy 16-cinnamylidene-S-androsten- 17-one, 3fl-phenylacetoxy-16-cinnamylidene-S-androsten-l7-one, 3 B(p-chlorophenoxyacetoxy)-16-cinnamylidene--5- androsten-17-one, 3fl-cinnamoyloxy-16-cinnamylidene-S-androsten-17-one or 3 8 nicotinoyloxy 16 cinnamylidene 5 androsten- 17-one, there can be obtained, respectively,

16- (Z-butenylidene) -5-androsten-3 B-ol- 17-one oxime,

2- 3- (S-furyl allylidene] -5-androsten-3;8-oll7-one oxime,

2- 3- (Z-thienyl) allylidene]-5-androsten-3B-ol-17-one oxime,

2-[3-(3-thienyl) allylidene]-5-androsten-3fi-ol-17-one oxime,

2-(4-rnethylcinnamylidene) -5-androsten-3}8-ol-17-one oxime,

2- (4-fluorocinnamylidene) -5-androsten-3B-ol-17-one oxime,

16-cinnamylidene-19-nor-5-androsten-3fl-ol-17-one oxime,

1 6-cinnamylidene-5 fiandrosten-3 a-ol-17-one oxime,

3B-acetoxy-16-cinnamylidene-S-androsten-17-one oxime,

3B-caproyloxy-16-cinnamylidene-S-androsten-17-one oxime,

3 B-(B-carboxypropionoxy}16-cinnamylidene-5 androsten-17-one oxime,

3 p3- fl-cyclohexylpropionoxy) 16-cinnamylidene-5 androsten-17-one oxime,

3 fl-benzoyloxy- 16-cinnamylidene-5-androstenl7-one oxime,

3 5- (p-nitrobenzoyloxy) -16-cinnamylidene-S-androsten- 17-one oxime,

3 3-phenylacetoxy-16-cinnamylidene-5-androsten-17-one oxime,

\ 3 5- (p-chlorophenoxyacetoxy) 16-cinnamylidene-5- androsten-17-one oxime,

Sfl-cinnamoyloxy-16-cinnamylidene-5-androsten-17-one oxime or 33 nicotinoyloxy 16 cinnamylidene 5- androsten-17-one oxime.

16 cinnamylidene 5 andr0Sten-3fi3-Ol-l7-0ne oxime (5.00 g.) was treated with 20 ml. of acetic anhydride in 40 ml. of pyridine, and the resulting product was recrystallized from a mixture of methylene dichloride and methanol to give 16 cinnamylidene 5 androsten-330l- 17-one oxime diacetate, colorless prisms, M.P. 238.0- 239.8 C. (corr.),- [a] =--196.2 (1% in chloroform);

ultraviolet maxima at 232 and 330 m,u (e=9,820 and 7 EXAMPLE 22 16 [3 (2 furyl)allylidene] androsten 3,8 ol- 17-one oxime [VIII; R is 2-furyl, R is CH Z is CH(OH-fi), A-S] was prepared from 45.63 g. of 16-[3- (2 furyl)allylidene]-5-androsten-3 8-o1-17-one (Example 19) and 16.40 g. of hydroxylamine hydrochloride according to the procedure described above in Example 6. The product was recrystallized from a mixture of methylene dichloride, methanol and ethyl acetate to give 16-[3-(2- fury1)allylidene] 5 androsten 3B ol 17 one oxime, tan blades, M.P. 238.8-240.0 C. (dec.) (corn), [a] =212.1 (1% in chloroform); ultraviolet maxima at 232, 331 and 353 m (e=29,700, 44,300 and 41,100).

EXAMPLE 23 16 [3 (2 furyl)allylidene] 5a androstan 313 01- 17 one oxime [VIII; R is Z-furyl, R is CH Z is CH(OH-fl)] was prepared from 133.2 g. of 16-[3-(2- furyl)allylidene] 5oz androstan-3fl-ol-17-one (Example 20) and 46.9 g. of hydroxylamine hydrochloride according to the procedure described above in Example 6. The product was cyclized as described below without further purification.

A sample of 16-[3-(Z-furyl)allylidene]-5a-androstan- 3;9-ol-l7-one oxime was treated with acetic anhydride in pyridine and the resulting product recrystallized from acetone to give 16[3-(2-furyl)allylidene]-5a-androstan- 3 3-0l-17-0ne oxime diacetate, brown prisms, M.P. 232.0- 233.2 C. (dec.) (corn), [a] =184.8 (1% in chloroform).

EXAMPLE 24 3 fi-hydroxy-iandrosteno 17, 16 b]-6-phenylpyridine [V; R is C H R is CH Z is CH(OH-,B), A-S] androsten 3/3 ol 17 one oxime (Example 21) (8.35 g.) was heated for two and one-half hours at 255-265 C. (15 mm.), uct was chromatographed on a column of 250 g. of silica gel. The column was eluted with ether-pentane 1:1 and the product recrystallized from a mixture of methylene dichloride and methanol to give 3B-hydroXy-5-androsteno [17,16-b] 6' phenylpyridine, colorless needles, M.P. 238.0-243.0 C. (corn), [a] =-17.3 (1% in chloroform).

By replacing the 16-cinnamylidene-S-androsten-3/3-ol- 17-one oxime in the foregoing preparation by a molar equivalent amount of l6 cinnamylidene 5 and the prodl 4 3fi-phenylacetoxy-16-cinnamylidene-5-androsten-17-one oxime, 3 3-(p-chlorophenoxyacetoxy)-16-cinnamylidene-5- androsten-17-one oxime, 3/3-cinnamoyloxy-l6-cinnamylidene-S-androsten-17'one oxime, or 3fl-nicotinoyloxy-16-cinnamylidene-S-androsten-17-one oxime,

there can be obtained, respectively,

3 fi-hydroxy-S -androsteno[ l7,16-b]-6-methylpyridine,

3 fl-hydroxy-5-androsteno[ 17, l 6-b]-6-( 3-furyl) pyridine,

3 ,B-hydroxy-S -androsteno 17, 1 6-b] -6'- (2-thienyl) pyridine,

3 fl-hydroxy-S-androsteno 17, 1 6-b] -6- 3-thienyl) pyridine,

3 B-hydroxy-S -androsteno 17, 1 6-b] -6- (p-tolyl pyridine,

3 fi-hydroxy-S -androsteno 17, 16-b]-6-(p-fluorophenyl) pyridine,

3fl-hydroxy-19-nor-5-androsteno[17,16-b]-6-phenylpyridine,

3fl-acetoxy-5-androsteno[17,16-b]-6-phenylpyridine,

3,8-caproyloxy-S-androsteno[ 17,16-b]-6-phenylpyridine,

3,6-(B-carboxypropionoxy)-5-androsteno[17,16-b]-6'- phenylpyridine,

319- (fl-cyclohexylpropionoxy) -5-androsteno 17, l6-b] -6- phenylpyridine,

3 )3-benzoyloxy-S-androsteno 17,16-b]-6'-phenylpyridine,

3 pl- (p-nitrobenzoyloxy) -5-androsteno[17,16-b]-6-phenylpyridine,

3 fl-phenylacetoxy-S -androsteno 17, 16-b]-6'-phenylpyridine,

3B-(p-chlorophenoxyacetoxy)-5-androsteno[17,16-b]-6- phenylpyridine,

3 ,B-cinnamoyloxy-5-androsteno 17, 16-b] -6-phenylpyridine, or

3,8-nicotinoyloxy-S-androsteno[17,16-b]-6-phenylpyridine.

EXAMPLE 25 3/8-acetoxy-5-androsteno[17,16-b] 6 phenylpyridine [V; R is C H R is CH Z is CH(OCOCH 3), A-5] was prepared by heating a mixture of 2.06 g. of 3,8-hydroxy-5-androsteno[17,l6-b]-6-phenylpyridine, 10 ml. of acetic anhydride and 20 ml. of pyridine for one hour on a steam bath. The product was recrystallized from a mixture of methylene dichloride and ethyl acetate to give 38- acetoxy-5-androsteno[17,16-b] 6' phenylpyridine, beige plate, M.P. 2l1.6220.6 C. (corn), [a =7 (1% in chloroform).

EXAMPLE 26 3-oXo-4-androsteno l7, 1 6-b] -6-phenylpyridine [V; R is C H R is CH Z is C=O, A-4] A solution of 4.00 g. of 3 3-hydroxy-5-androsteno[17, 16-b]-6-phenylpyridine (Example 24) and 40 ml. of cyclohexanone in 260 ml. of toluene was distilled, and two fractions of toluene (10 ml. and 50 ml.) were collected. Aluminum isopropoxide (4.08 g.) was dissolved in the 50 ml. portion of toluene and added during a period of seventy minutes to the refluxing solution while toluene was slowly distilled ofi. The reaction mixture was refluxed for forty minutes longer, cooled, and 40 ml. of saturated potassium sodium tartrate solution was added. The reaction mixture was steam distilled for one hour, 0.8 liter of distillate being collected. The resulting mixture was extracted with methylene dichloride, and the extracts were washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from a mixture of methylene dichloride and methanol to give 3-oxo-4-androsteno[17,16-

EXAMPLE 27 3 fi-hydroxy-S-androsteno 17, 16-b] -6'(2-furyl) pyridine [V; R is 2-furyl, R is CH Z is CH(OH-) A-S] EXAMPLE 28 3 oxo-4-androsteno[17,16-b]-6-(2-furyl)pyridine [V; R is 2-furyl, R is CH;.,, Z is A-4] was prepared by O'ppenauer oxidation of 3fl-hydroxy-5-androsteno[17, 16-b]-6'-(2-furyl)pyridine (Example 27) according to the procedure described above in Example 26. The product was recrystallized from a mixture ofmethylene dichloride and ethyl acetate to give 3-oxo-4-androsteno[17, 16-b]-6-(2-furyl)pyridine, tan rods, M.P. 222.8-225.6 C. (dec.) (corn), [a] =+222.2 (1% in chloroform); ultraviolet maxima at 242 and 309 m (c=19,500 and 18,500).

EXAMPLE 29 3 B-hydroxy-S a-androstano 17, 1 6-b] -6'-( Z-furyl) pyridine [IV; R is C H R is CH Z is CH(OH-}8)] 16 [3- 2-furyl)allylidene]-5a-androstan-3B-ol-17-one oxime (Example 23) (41.0 g.) was heated from 190 to 230 C. over a period of one hour and then at 220230 C. under water aspirator vacuum for four hours. The benzene soluble product was chromatographed on silica gel and eluted with ether-pentane 1:1. The product was recrystallized from acetone to give 3B-hydroxy-5-androstano[17,16-b]-6-(2-furyl)pyridine, biege-colored blades, M.P. 235.6-237.2 C. (corn), [a] =+94.8 (1% in chloroform) 3,8 hydroxy 5a-androstano[17,16-b]-6-(2-furyl)pyridine when heated with acetic anhydride in pyridine and the product recrystallized from an acetone-methanol mixture gave 3B-acetoxy-5 a-androstanoi17,16-b]-6'-(2-uryl) pyridine, M.P. 181183 C. (uncorr.).

EXAMPLE 3 oxo 5a-androstano[17,16-b]-6'-(2-furyl)pyridine [V; R- is 2-furyl, R is CH Z is C=O] was prepared by the Oppenauer oxidation of 3 B-hydroxy-S a-androstano- [l7,l6-b]-6-(2-furyl)pyridine (Example 29) by the procedure described above in Example 26. The product was recrystallized from a mixture of methylene dichloride and acetone to give 3 oxo 5a androstano[l7,16-b]-6'-(2- furyl)pyridine, M.P. 216-228 C. (uncorr.).

EXAMPLE 31 3-oxo-4-androsteno[17,16-b]pyridine [V; R is H, R 'is CH Z is C=O, 1341 3 w oxo 4 androsteno[17,16-b]-6'-(2-furyl)pyridine was subjected to ozonolysis by the procedure described above in- Example 16, and the resulting 3-oxo-4-androsteno[17,l6-b]-6-carboxypyridine was decarboxylated by heating it at 220230 C. for three hours. The product was dissolved .in methylene dichloride and chromatographed on a column of 200 g. of silica gel. The column was eluted with pentane-ether and then with ether. The latter brought out the desired product which was recrystallized with a mixture of methylene dichloride and ethyl acetate to give 3-oxo-4-androseno[17,16-b1pyridine, M.P. 199201 C. (uncorr.); ultraviolet maxima at 242, 268 and 276 mp. (e=l7,900, 8,050 and 5,200); infrared absorption at 3.35, 3.44, 6.04, 6.23, 6.29, 6.36; 6.83 and 6.95 1.

EXAMPLE 32 3B hydroxy 5ot-androstano[17,16-b]6-carboxypyridine [V; -R is COOH, R is CH Z is CH(OH-/3)] was prepared by ozonolysis of 7.83 g. of 3;8-hydroxy-5a.-andro stano[17,16 b] 6'-(2-furyl)pyridine (Example 29) according to the procedure described above in Example 16. The product was recrystallized from a mixture of methylene dichloride and methanol to give 3fi-hydroxy-5d-an drostano[17-16-b]-6-carboxypyridine containing /2 mole of methanol of crystallization, colorless prisms, M.P. 220.0-222.8 C., [a] =+83.8 (1% in chloroform); ultraviolet maxima at 233 and 277 m (e==7,000 and 8,100).

EXAMPLE 33 3/3 hydroxy 5u-androstano[17,16-b]-6-carboxypyridine (Example 32) (3.54 g.) was heated from 190 to 220? C. during one hour and then heated at 222 C.'for one hour under nitrogen. The resulting product was dissolved in methylene dichloride and chromatographed on a col umn of g. of aluminum oxide. The column was eluted with 'pentane-ether and then with ether. The latter brought out the desired product which was recrystallized from a mixture of methylene dichloride and acetone to give 3p-hydroxy-5u-androstano[17,16-b]pyridine, colorless plates, M.P. 195.0-195.8 C. (corn), [a] ==+41.5 (1% in chloroform).

EXAMPLE 34 3-oxo-5ot-androstano[17,16-b1pyridine [V; R is H, R is CH Z is 0:0] was prepared by ozonolysis and decarboxylation of 3-oxo-5a-androstano[17,16-b]-6' (2-furyl) pyridine (Example 30) according to the procedure described above in Example 16. The product was dissolved in methylene dichloride, chromatographed on aluminum oxide and eluted with pentane-ether 1:1. The product was recrystallized from a mixture of acetone and hexane and then from acetone to give 3-oxo-5a-androstano[17,16-b] pyridine, M.P. 174.2175.2 C. (corn), [a] =+69.Z (1% in chloroform).

EXAMPLE 35 (a) A.solution of 3.18 g. of 17fl-hydroxy-2-hydroxymethylene-5a-androstan-3-one, 1.01 g. of triethylamine, 0.158 g. of paraformaldehyde and 0.38 g. of p-toluenesulfonic acid monohydrate in 20 ml. of absolute ethanol was refluxed for sixteen hours. The mixture was cooled and seeded with a trace of the desired product to causeseparation of 2a,2a-methylenebis(l7,8-hydroxy-5a-androstam 3-one), colorless needles, M.P. 313-315 C. (uncorr.) when recrystallized from methanol; [-oc] =-0.4 (1% in chloroform); ultraviolet maximum at v284 ,mp. (6:642); diacetate, M.P. 303305 C. (uncorn) (from methanol). 1

(b) Bis(17B-acetoxyandrostano[3,2 b:2',3' e] )pyridine- [IX; R" is H, Y is COCH ].-A solution of 1.31 g. of 2a,2a-methylenebis(17p-hydroxy-5a-androstan-3-one), 0.61 g. of hydroxylamine hydrochloride, 20 ml. of pyridine and 20 ml. of absolute ethanol was heated at reflux for four hours and then quenched in 300 ml. of water. The resulting amorphous solid comprising bis(17/3-hydroxyandrostano[3,2-b:2,3'-e])pyridine was warmed on a steam bath for two hours with 8 ml. of acetic anhydride where R is a member of the group consisting of hydrogen, carboxy, loWer-alkyl, phenyl, furyl and thienyl; R is a member of the group consisting of hydrogen and methyl; Z is a member of the group consisting of C=O, CH(OH-p), C(lower-alkyl) (OHrfi), CH(OAcyl-B), and C(loWer-alkyl) (OAcyl-fi), Acyl being carboxylic acyl having from 1 to carbon atoms; (R) compounds of the above formula having a double bond in the 4,5-position; and (C) compounds of the above formula having double bonds in the 4,5- and the 6,7-po'sitions.

2. 17fi-acetoxy-5wandrostano 3,2-b pyridine. 3. 17fi-hydroxy-17a-methyl-5a-androstano[3,2 b]pyridine.

4. The process for preparing a compound selected from the group consisting of (A) compounds of the formula wherein R is a member of the group consisting of loweralkyl, phenyl, furyl and thienyl; R is a member of the group consisting of hydrogen and methyl; Z is a member of the group consisting of CH(rOH-,B), C(loWer-alkyl) (OH-,8), CH(OAcyl-.fi), and C(lower-alkyl)(OAcyl-;8), Acyl being carboxylic acyl having from 1 to 10 carbon atoms; (B) compounds of the above formula having a double bond in the 4,5-position; and ((3) compounds of the above formula having double bonds in the-4,5- and the 6,7-positions, which comprises heating a compound selected from the group consisting of (A) compounds of the formula compounds of the latter formula having a double Bond in the 4,5-position; and (Cfcompounds of the latter forinula'having d'ouble "-borids" in 'tli"'4,5--and the 6,' 7-posi-' Hons" v I. w i l r t 5: The process forpr'eparing' a'coi'npound selected from the group consisting of (A) compounds of the formula wherein R is hydrogen; R is a member of the group consisting of hydrogen andm'ethyl; Z is a member" of the group consisting of C=O, CI I-(OH-fi), C(lower=alkyl) (OH- 3), 'GH(0Acyl and C(lowe r-'alkyl)(OAcyl 8), Acyl being carboxylic acyl having from 1"'-to- 10 carbon atoms; (B) compounds of the above" formula having a wherein R is a member of the group consisting of loweralkyl, phenyl, furyl and thienyl; R1. is a member :of the group consisting of hydrogen and mlthyl; -X is a mem ber of the group consisting of O, HON:and AcylO-N; Z is a-me mber of the' group consisting of CH(OH- 3), C(IOWer-aIkyIXOH-fi); CH(OAcyl!:/8), and C(lower alkyl) (OAcyl-fl), Acyl being carboxylic acyl having from 1 to 10 carbon atoms;- (B) compounds o ffthe above forniula having a double.- bond in thet 4,5-position; and- (C) compounds of the above formula having double bonds in the 4,5- and the 6, 7-p os itions. r r

7. 2-cinnamylidene-5a-androstan-l7fl-ol-3-one. t

8. 17a-methyl-2-[3-(2-furyl)allylidene] -.5a-androstan- 17p-ol-3-0ne. I "'QY Ihe process for preparing a compound selected from the group consisting of"(A)' compounds of the formula atoms; (B) compounds of the above dou'ble bond in the 4,5-positio'n; and (C) compounds of -x y;-l ,"-:l v I theiaboye, formula having double bonds .m the 4,5- and a compoundselected from the group consisting of, (A) the 6,7-positions, which comprises reacting in the presence compounds of the formula V ofastrongbase a compound selected from the group con- 7 t. sistmgof (A) compounds of the formula CH3 I 5 g N-on CH3 i I i I oHoH=oHR Q 1 v v I p O 2 I V T h h b d herein R R and Z avet e meanings given a ove; an (B) compounds of the latter formula having a double W a bond int-the 4,5-position; and (C) compounds of the latter P i latter formula havmg a double formula-having double bonds in the 4,5- and the 6,7- t e positionsvjwithva compound of the formula t 14. The process for preparing a compound selected v v t m from the group consisting of (A) compounds of the i formula t wherein R is a member of the group consisting-of loweralkyl, phenyl, furyl and thienyL, R 10. A compound selected from the group consisting of CH3 (A) compounds of the formula t 28 N CH 1 I R N 30 v z i R i wherein R is hydrogen; R is a member of the group V consisting of'hydrogen and methyl; Z is a member of the group consisting of C=O, CH(OH) and CH(OAcyl),

40 Acyl being carboxylic acyl having from 1 to 10 carbon wherein R is a member of the group consisting of y atoms; (B) compounds of the above formula where Z 8 Y, 31 P y n and y is C=O and having a double bond in the 4,5-position; and is a mem er of the group C nsi g f y m and (C) compounds of the above formula where Z is y i a member o g p ponsisting CH(OH) or CH(OAcyl) and having a double bond in and WU, y bemg carboxyllc y 4 the 5,6-position, which comprises ozonizing a compound having from 1 to 10 carbon atoms; (B) compounds of of the above formula where R is 2-furyl and decarboxylthe above formula where Z' is C=O and ha ing a double ating by heating the resulting compound of the above bond in the 4,5-position; and (C) compounds of the formula whereinRis carboxy.

abov fo mu a Where is Y 15. A compound selected from the group consisting of having a double bond in the 5,6-position. (A) compounds of the formula 11. 3 B-hydroxyandrostano[ 17 ,16-b] pyridine. 12. 3-oxoandrostano[ 17,1 6-b] pyridine.

13. The process for preparing a compound selected 3 from the group consisting of (A) compounds of the f formula R CHCH=GHR out l i o0 i L wherein R is a member of the group consisting of loweralkyl, phenyl, furyl and thienyl; R is a member of the group consisting of hydrogen and methyl; X is a member I ,v 1 of the group consisting of HO-N and Acyl--O--N; Z

wherein R is a member of the group consisting of loweris a member of the group consisting of CH(OH) and alkyl, phenyl, furyl and thienyl; R' is a member of the 7 CH(OAcyl), Acyl being carboxylic acyl having from 1 group consisting of hydrogen and methyl; Z is a member to 10 carbon atoms; and (B) compounds of the above of the group consisting of CH(OH) and CH(QAcyl), formula having a double bond in the 5,6-position.

Acyl being carboxylic acyl having from 1 to 10 carbon 16. 16-cinnamy1idene-5-androsten-3[3-ol-17-one oxime.

atoms; and (B) compounds of the above formula having I 17. l6-[3-(2-furyl)allylidene]-5ot-androstan-313- 01-17 a double bond in the 5,6-position, which comprises heating one.

21 18. A process for preparing a compound selected from the group consisting of (A) compounds of the formula wherein R" is a member of the group consisting of hydrogen and lower-alkyl, and Y is a member of the group consisting of hydrogen and carboxyli-c acyl having from 1 to 10 carbon atoms.

20. A- process for preparing a compound of the formula which comprises reacting with hydroxylamine a compound of the formula RI! CH3 goo wherein R" is a member of the group consisting of hydrogen and lower-alkyl, and Y is a member of the group consisting of hydrogen and carboxylic acyl having from 1 to 10 carbon atoms.

21. A compound according to claim 1 wherein R is hydrogen, phenyl or 2-furyl, and R is methyl.

22. A compound according to claim 6 wherein R is phenyl or 2-furyl, and R is methyl.

23. A compound according to claim 10 wherein R is hydrogen, carboxy, phenyl or 2-furyl, and R is methyl.

24. A compound according to claim 15 wherein R is phenyl or 2-furyl, and R is methyl.

References Cited UNITED STATES PATENTS 3,178,409 4/1965 Pike.

HENRY A. FRENCH, Primary Examiner.

f2;; UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent 5. 409609 Dated November 5, 1968 Invented Theodore C. Miller It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

[- Column 1, line 2, in title, "ADROS'IANO-" should read --ANDROSTANO- Column 2, line 54, after "of" insert --the oxime, Column 4, lines 70-75, left-hand portion of formula,

II N

HOCH should read HOCH Column 7, line 21, t-androstarr" should read -4-androstenline 37, "4-androstan" should read +-androstenline 50, "infared" should read --infrared-. Column 8, line 23, "ea-245C. should read -1- 220-2490. line 57, "l7a-hydroxy-" should read --l7B-hydroxy- Column 9, line 65, "pyrdine. should read --pyr1d1ne.-. Column 10, line 27, "15,000" should read --15, lOO--. Column 11, line 62, "5a-androsten-" should read -5a-androstan- Column 12, line 20, "5B-androsten" should read --5B-androstanline 49, "5Bandrosten-" should read --5Bandrostan- Column 13, line 32, "184. 8 should read -l84.8 Column 1a, line 49, "plate, should read "plates, and "H15 should read "[613 Column 15, line 35, "IV; should read --v;--; and "CH should read --CH line 42, "5-andro.-" should read --5a-andro- Column 16, line 2, "4-androseno" should read --4-androsteno--.

SIGNED AN) .i-"MEU AUG 1 81590 J Alum LLIAM E.

Gomis 1 Edmd M. W4 3:- s of Attesting Officer 

